Methods for treating adhesive capsulitis

ABSTRACT

The invention relates to the discovery that collagenase injections are effective in lyse the collagenous adhesions in the shoulder and treat the disorder, adhesive capsulitis. As such, the invention relates to methods of treating or preventing adhesive capsulitis, or frozen shoulder, in a patient in need of such treatment comprising injecting or otherwise delivering an effective amount of collagenase to the collagenous adhesions in the shoulder. The invention also relates to the use of collagenase in the manufacture of a medicament to treat adhesive capsulitis.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/645,772, filed on Jan. 21, 2005, U.S. Provisional Application No.60/677,440, filed on May 3, 2005 and U.S. Provisional Application No.60/719,470, filed on Sep. 22, 2005. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

GOVERNMENT SUPPORT

The invention was supported, in whole or in part, by a grant MO1RR10710from the National Institutes of Health. The Government has certainrights in the invention.

BACKGROUND OF THE INVENTION

Adhesive capsulitis (frozen shoulder) is a clinical syndrome of severepain and significantly decreased shoulder motion which may occuridiopathically, after trauma or affect patients with diabetes and/orthyroid disorders. The duration of the disorder may be from months toyears and severely affect the quality of life. Lengthy physical therapy,sometimes including cortisone injections and/or manipulation underanesthesia and/or shoulder arthroscopy, currently are the standards oforthopedic care. However, more effective therapies are needed.

SUMMARY OF THE INVENTION

The invention relates to the discovery that collagenase injections areeffective in lyse the collagenous adhesions in the shoulder capsule andtreat the disorder, adhesive capsulitis. As such, the invention relatesto methods of treating or preventing adhesive capsulitis, or frozenshoulder, in a subject in need of such treatment comprising injecting orotherwise delivering an effective amount of collagenase to thecollagenous adhesions in the shoulder. The invention also relates to theuse of collagenase in the manufacture of a medicament to treat adhesivecapsulitis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph that reports the improved mobility, or activeelevation, in twelve patients who received a third collagenaseinjection.

FIG. 2 is a line graph of the means of normal shoulder motion vs.collagenase dose groups.

FIG. 3 is a line graph of the means of shoulder motion after a 0.58 openlabel collagenase injection.

FIGS. 4A-4EE are line and bar graphs depicting the data obtained in theclinical trial described herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the discovery that collagenase injections areeffective in lyse the collagenous adhesions in the shoulder capsule andtreat the disorder, adhesive capsulitis. As such, the invention relatesto methods of treating or preventing adhesive capsulitis, or frozenshoulder, in a subject in need of such treatment comprising injecting orotherwise delivering an effective amount of collagenase to thecollagenous adhesions in the shoulder capsule. The invention alsorelates to the use of collagenase in the manufacture of a medicament totreat adhesive capsulitis.

Collagenase injections have been proposed for the treatment of diseasessuch as Duptyren's disease and Peyronie's disease. Both diseases areassociated with collagen plaques or cords. Wegman, Thomas L., U.S. Pat.No. 5,589,171, Dec. 31, 1996, U.S. Pat. No. 6,086,872, Jul. 11, 2000 andU.S. Pat. No. 6,022,539, Feb. 8, 2000, which are incorporated herein byreference.

Collagenase is an enzyme that has the specific ability to digestcollagen. A preferred form of collagenase is derived from fermentationby Clostridium histolyticum, and is purified by a chromatographictechnique.

Sterilized lyophilized collagenase powder is commercially availablehaving a minimum assay of 50 ABC units per mg. The assay may rangeconsiderably above that from batch to batch, but is taken into accountin determining the weight of powder to use with a pharmaceuticallyacceptable carrier, e.g. normal saline, in preparing a desiredconcentration for treatment.

A preferred collagenase composition comprising a mixture of collagenaseI and collagenase II in a mass ratio of about 1 to 1 and having specificactivity of at least about 700 SRC units/mg, such as at least about 1000SRC units/mg, more preferably at least about 1500 SRC units/mg. One SRCunit will solubilize rat tail collagen into ninhydrin reaction materialequivalent to 1 nanomole of leucine per minute, at 25° C., pH 7.4.Collagenase has been described in ABC units as well. This potency assayof collagenase is based on the digestion of undenatured collagen (frombovine tendon) at pH 7.2 and 37 degrees C. for 20-24 hours. The numberof peptide bonds cleaved are measured by reaction with ninhydrin. Aminogroups released by a trypsin digestion control are subtracted. One netABC unit of collagenase will solubilize ninhydrin reactive materialequivalent to 1.09 nanomoles of leucine per minute. 1 SRC unit equalapproximate 6.3 ABC unit or 18.5 GPA unit.

The collagenase is preferably administered via injection in a liquidcarrier that is pharmaceutically acceptable. Preferably the carrier doesnot interact or deactivate the collagenase. Examples are normal saline,aqueous NaCl/CaCl2 buffer (e.g., containing 0.9% NaCl and 2 mM CaCl₂),aqueous dextran solution, and aqueous hetastarch solution. For example,the lyophilized formulation can contain 0.1 mg lactose monohydrate per1,000 ABC units. Each glass vial used below contained 5,150 ABC units ofenzyme.

In accordance with the invention, collagenase in a liquid carrier isinjected into a collagen adhesion within the shoulder capsule. Theamount and concentration of collagenase used are effective to soften andrelax or rupture the adhesion.

The total volume of liquid injected preferably does not exceed about0.50 ml. A smaller volume down to about 0.25 ml to about 0.1 ml isusually more preferred.

Preferably, the injection is a sterile one given between the interval ofthe deltoid and pectoral muscles. An anesthesia injection of 5-10 mlsterile 1% lidocaine preferably precedes the collagenase injection forthe comfort of the patient.

The total dosage is preferably injected in one portion, although two ormore portions at the same or different points into the shoulder capsuleare possible, preferably intralesionally, or intra-adhesionally. Theobjective of these procedures is to assure good distribution of thecollagenase within a small volume of the adhesion. Preferably, thepatient wears a sling to immobilize the shoulder for approximately 5-6hours post injection. Patients perform at home physical therapy for atleast one month to assist in the return of normal range of shouldermotion.

In other embodiments, the collagenase can be administered locally andtopically (e.g., via a transdermal patch or topical cream or ointment),preferably at site proximal to the affected shoulder or can beadministered via an implant (e.g., microcapsules or microspheres whichrelease the collagenase over time).

The subject can be any animal, preferably a mammal or human patient.Examples of animals that can be treated according to the inventioninclude domestic animals (such as cats, dogs, etc.), farm animals (suchas horses, cows, pigs, etc.) and exotic animals (such as monkeys, apes,etc.). Preferred human patients are those that have decreased shouldermotion which occurred idiopathically, after trauma or patients withdiabetes and/or thyroid disorders.

In one embodiment, the patient is characterized as having extremelydecreased shoulder motion in all planes to include active elevation,active internal rotations (spine level reached by the thumb behind theback), active external rotation, passive elevation, passive externalrotation at the side, passive external rotation at 90 degrees, functionscores. Pain is increased to a level where it interferes with activitiesof daily living and diminishes the quality of life. The invention canachieve improvement in all planes of motion of the shoulder or decreasedpain or alleviation of another symptom of the disorder.

In cases where results of a single treatment are considered inadequate,the same procedures, total amount of collagenase and concentration maybe repeated. Successful clinical results were achieved with repeatedinjections at 4 to 6 week intervals.

EXPERIMENTAL Example 1

Methods

Forty patients entered the study protocol, 11 males and 29 females, meanage 52±8.9 years. At the time of initial presentation, the mean lengthof time that all patients had adhesive capsulitis was 16 months (range2-144 mo). Eighteen patients were idiopathic, six patients were Type 1and six patients were Type 2 diabetics, five patients hadhypothyroidism, three patients had hypothyroidism and diabetes, and twopatients were affected by post-traumatic adhesive capsulitis. Followinga 10 ml 2% lidocaine injection for local anesthesia, all patientsreceived a first, random placebo controlled double blind injection ofeither 0.145 mg, 0.29 mg or 0.58 mg Clostridial collagenase or placebo(0.9% saline containing 2 mM calcium) directed at the anterior capsule,0.5 ml total volume. Patients were evaluated serially for one monthbased on the American Society of Shoulder and Elbow Surgeons ShoulderEvaluation form which scores pain, shoulder motion, strength, stabilityand function. Shoulder motion evaluations were measured in degrees andconsisted of: active/passive elevation, active/passive externalrotation, passive external rotation at 90 degrees and active internalrotation (spine level reached by thumb posteriorly). If the shouldermotion scores or pain scores were not statistically significant frombaseline values, patients had the option of proceeding to additionalopen label 0.58 mg collagenase injection(s) administered at 4-6 weekintervals. Nine patients received only one (random placebo double blind)injection, 30patients received a second open label 0.58 mg collagenaseinjection. The control treatment code for the first random placebodouble blind injection (dose response) may not be unmasked until thetotal of 60 patients has been enrolled. However, the results of the openlabel collagenase injections have shown clear and significant merit. Allpatients were followed, using the shoulder evaluation form, at two,three, six, nine, 12 and 24 months post their last injection. Meanlength of follow-up was 10.8±8.2 months. Statistical analysis consistedof testing the mean change from baseline shoulder evaluations by thestudent's t test.

Results

Thirty of the 40 patients required a short series of repeat open label0.58 mg collagenase injections after a first random, placebo, doubleblind injection. Table 1 shows the mean increases in should range ofmotion, function and pain in the affected shoulders comparing baselineparameters to the one month post 2^(nd) and 3^(rd) injection follow-ups.All increases were statistically significant, p<0.0001. Diabeticpatients (n=15) showed smaller increases from baselines in active andpassive external rotation, internal rotation (spine level) and passiveelevation when compared to idiopathic patients (n−18). For example, foractive external rotation at one month post the second injection, themean increase in idiopathic patients was 31.4°±14.1° but only20.5°±15.50 in diabetic patients (p=0.02). Patients with hypothyroidismand post-trauma patients showed equal rates of recovery of shouldermotion compared to idiopathic patients. Improvements in should motion,pain and function were sustained in the longer term, mean length offollow up 10.8±8.2 months.

Adverse effects of injections included tenderness at the injection sitein all patients and biceps ecchymosis in approximately two-thirds ofpatients. These resolved without even in 7-14 days. TABLE 1 Treatedshoulder and contralateral shoulder at baseline 2^(nd) Injection 3^(rd)Injection (n = 30) (n = 12) Active elevation 30.8° ± 15.7° 36.8° ± 13.5°Passive elevation 25.4° ± 16.5° 25.8° ± 17.5° Active external rotation27.4° ± 15.4° 39.0° ± 16.3° Passive external rotation 37.2° ± 22.0°40.3° ± 22.2° Passive external rotation at 90° 21.8° ± 18.9° 27.8° ±15.6° Internal rotation (spine level) +5 levels ± 3.8 +6 levels ± 4.8levels levels Function +20 points ± 8 +23.5 points ± 11 points pointsPain 4 (slight) 4 (slight)Conclusions

After a first random, placebo, double blind injection, the majority ofpatients (30 of 40) required a short series of open label (0.58 mg)collagenase injections before significant improvements were seen inshoulder motion, pain and function. Therefore, despite the fact that thefirst injection treatment code for dose response is still masked to theinvestigators, it is clear that collagenase injection of adhesivecapsulitis has shown significant merit. Open label collagenase treatmentresulted in significantly reduced time in return to pain free functionwhen compared to the standard Orthopaedic care, which can last for manymonths or even years. This Phase 2 study has shown that collagenaseinjection of the shoulder capsule is a safe and effective method oftreatment for adhesive capsulitis, which warrants continuedinvestigation within the FDA regulatory process.

Example 2

The purpose of this FDA regulated, prospective, Phase II, random,placebo controlled, double blind, dose response study was to develop anonoperative method for treatment of adhesive capsulitis (frozenshoulder) using collagenase injection therapy.

Sixty patients entered the study protocol, 47 females and 13 males, meanage 52 years, mean duration of adhesive capsulitis, 17 months. Allpatients received a first, random, placebo controlled, double blind,extra-articular injection of either physiologic saline (n=15), or 0.145mg (n=16), or 0.29 mg (n=15), or 0.58 mg (n=14) collagenase, 0.5 mltotal volume, directed at the anterior shoulder capsule. Patients wereserially evaluated for 1 month for shoulder range of motion in allplanes, pain, and function. At 1 month, if motion, pain and functionalscores were not significantly different from baseline, patients had theoption of receiving up to four additional 0.58 mg collagenaseinjections, given six weeks apart.

In the open-label portion of the study, for the first open-label course,n=13, 12, 9, and 10 for, respectively, placebo, 2,500 unit, 5,000 unit,and 10,000 unit treatment groups, except for active elevation andpassive elevation for which n=9 for the 5,000 unit group. For the secondopen label course, n=7, 7, 4, and 6 for, respectively, placebo, 2,500unit, 5000 unit, and 10,000 unit treatment groups. For subjects with thecontralateral shoulder measured at baseline, in the first open labelcourse, n=10, 8, 8, and 8 for, respectively, placebo, 2,500 unit, 5000unit, and 10,000 unit treatment groups. For the second open labelcourse, n=4, 5, 3, and 5 for, respectively, placebo, 2,500 unit, 5000unit, and 10,000 unit treatment groups for subjects with contralateralshoulder measurements at baseline. Three subjects in the data receivedhad data for a third.

Results of the random placebo controlled, dose response study showedthat there were statistically significant differences in drug treatmentvs. placebo in restoration of normal shoulder motion and function, withminimal pain and the 0.58 mg dose trending to be the most efficacious. Amajority of patients required second (n=19) and third (n=19), open label0.58 mg collagenase injections and continued to show significantimprovements in motion, function and pain. This study has shown that ashort series of collagenase injections of the shoulder capsule foradhesive capsulitis is a safe and effective method of treatment whichwarrants continued investigation within the FDA regulatory process.

Sixty subjects completed the nominal day 30 visit in the double-blindphase and provided data for statistical analysis. The sample sizes forplacebo, 2500 units, 5,000 units, and 10,000 units treatments were,respectively, 15, 16, 15, and 14. Of those 60 subjects, 46 had data forthe contralateral shoulder at baseline: 12, 10, 12, and 12 subjects for,respectively, the placebo, 2,500 units, 5,000 units, and 10,000 unitstreatment groups. TABLE 1 Treated shoulder and contralateral shoulder atbaseline Contralateral Treated shoulder shoulder (n = 46) (n = 60)Active elevation (degrees) 166.9 ± 12.4  112.1 ± 19.6  Active externalrotation (degrees) 77.1 ± 14.0 26.6 ± 16.7 Active internal rotation(spine level) 14.4 ± 3.6   5.3 ± 2.34 Passive elevation (degrees) 175.3± 8.1  130.4 ± 17.2  Passive external rotation (degrees) 86.1 ± 10.028.0 ± 18.0 Passive external elevation @ 90° 103.8 ± 11.1  69.4 ± 15.3(degrees) Function score (0-60 scale) 60.0 ± 0   32.0 ± 7.6  Pain score(0-5 scale) 5.0 ± 0   2.0 ± 0.9

For the protocol-defined success criteria, none of the outcome measuresapproached statistical significance for any active treatment compared toplacebo. One might wonder if the protocol-defined success criteria,drawn from published standards, are too strict for the population inthis study. Comparison of the contralateral shoulder means to thepublished standards seems to not support that. For example, theprotocol-defined criteria for active elevation and active internalrotation (spine level) are 160 degrees and 10 degrees, respectively,but, from Table 1, the subjects in this study had better functionalityat baseline in the contralateral shoulder for these two outcome measuresthan the published standards stipulate. TABLE 2 Means at the 30-daydouble-blind visit adjusted for baseline of treated shoulder Placebo2,500 u 5,000 u 10,000 u (n = 15) (n = 16) (n = 15) (n = 14) Activeelevation 124.5 131.9 130.2  139.7 (degrees) Active external rotation42.4 42.3   52.6 * 48.6 (degrees) Active internal rotation 8.0 8.4  8.47.9 (spine level) Passive elevation 145.5 145.2 148.6  145.9 (degrees)Passive external rotation 44.5 49.3 55.6 59.5 (degrees) Passive externalelevation 83.8 81.7 89.4 87.9 @ 90° (degrees) Function score 43.0 44.248.6 49.8 (0-60 scale) Pain score 3.3 3.4  3.9 3.4 (0-5 scale)* p ≦ 0.05

The analysis of covariance adjusted the double-blind phase treatmentmeans for their different baseline values so that, in effect, eachtreatment had the same mean for the treated shoulder at baseline. Withthat adjustment, four of the eight outcome measures analyzed showedactivity for the 5,000 unit or 10,000 unit treatments (Table 2). The10,000 unit dose showed activity, relative to placebo, for activeelevation, passive elevation, and function score. The 5,000 unittreatment showed activity for active external rotation. It is worthnoting that for each of those four outcome measures, subjects in theplacebo group had, on average, less favorable or just about lessfavorable, outcomes than any group receiving active treatment.

The exploratory analyses of the open-label data supported results of theanalysis of covariance of the double-blind data.

After one open-label course, subjects had received a total of 10,000units, 12,500 units, 15,000 units, or 20,000 units of collagenase,depending on their treatment group in the double-blind phase. For activeelevation, the change from the treated shoulder baseline or thecontralateral shoulder baseline is consistent with an active collagenasetreatment. For example, relative to the treated shoulder baseline,active elevation improved by 43.6 degrees for the 10,000 unit group butonly 28.3 degrees for the placebo group. For function score, theimprovement for the 10,000 unit group was 21.6 points on the 60-pointscale versus an improvement of 20.6 points for the placebo group. Someoutcome measures did show more improvement for the placebo group thanfor the collagenasetreated groups. For example, for active externalrotation, the group that received placebo in the double-blind phase(n=15) had a change from baseline of 35.2 degrees after one course ofopen-label treatment (n=13 subjects continued from the double-blindphase) but the group that received 10,000 units in the double-blindphase (n=14) had a change from baseline after an additional 10,000 unitsof only 27 degrees (n=10 continued from the double-blind phase).

Discussion

The study set out to demonstrate that a single collagenase injection of2,500, 5,000, or 10,000 units is more efficacious than placebo injectionfor adhesive capsulitis. The protocol stipulates dichotomous “success”criteria for 11 outcome measures and those clearly were not met. Theprotocol also stipulates a more sensitive analysis of the data using theanalysis of covariance and that approach does provide evidence thatcollagenase had activity in this study.

Eight of the outcome measures were analyzed with the analysis ofcovariance and four of the eight did present evidence of collagenaseactivity. Active elevation, passive elevation, and function score hadp-values <0.05 for the comparison of placebo to the 10,000 unittreatment. For active external rotation, the 5,000 unit treatment had ap-value <0.05, although the 10,000 unit dose did not. For passiveexternal elevation at 90°, placebo has an adjusted mean of 83.8 degreesversus an adjusted mean of 87.9 for the 10,000 unit treatment althoughthe p-value for this difference is not less than 0.05. The remainingthree outcome measures: active internal rotation (spine level), passiveelevation, and pain score were not at all sensitive to any collagenaseeffect, with placebo and collagenase very similar.

The gold standard in clinical trials is protocol-specified analysis ofdata collected in a randomized, placebo-controlled, double-blind studyand with that gold standard, as discussed above, there is evidence thatcollagenase has activity in adhesive capsulitis.

Aside from evidence collected with the gold standard, supportive orexploratory analysis can provide important corroboration. The open-labelportion of this study, particularly for active elevation and functionscore, does corroborate the double-blind portion. The open label portionof the study suggests that additional injections may be of benefit.

Conclusion

The outcome measures of active elevation, active external rotation,passive elevation, and function score, as analyzed in the analysis ofcovariance of the double-blind data, do show evidence of activity inadhesive capsulitis of the shoulder. The three collagenase dosesadministered in this study did not meet the protocol-defined criteriafor “success” therefore it cannot be concluded that a single injectionof collagenase, even at the highest dose of 10,000 units, isefficacious.

Example 3

At one month after the first random, placebo controlled, double blindinjection in all 60 patients, shoulder motion was improved, but not tonormal values. The highest collagenase dose (0.58 mg) trended as themost effective (FIG. 2). Function scores were 70% of normal for placebo,73% for 0.145 mg collagenase, 81% for 0.29 mg and 83% for 0.58 mg. Painscores were 66% of normal for placebo and the 0.145 mg dose and 74% ofnormal for both the 0.29 mg and 0.58 mg doses. The spine levels reachedbehind the back (active internal rotation) were L3 for placebo and L2for all collagenase doses. Normal spine level was T8. Fourteen patientsrequired only the first injection because they responded to normal afterone month.

Twenty three patients had a second open label injection consisting of0.58 mg collagenase. Improvements in active elevation, active externalrotation, active internal rotation, passive elevation, passive elevationat the side, passive elevation at 90 degrees, function and pain scorewere significant (p<0.O1) and dramatic, beginning atone day post theopen label injection (FIG. 3). Baseline values are denoted in FIG. 3 atday 0. Normal values are on the y axis. At one month post injection, allparameters reached normal values, based on the means of the unaffectedcontralateral side. Slight improvements in all parameters occurredthroughout the succeeding months of follow-up. Twenty patients went onto a third open label, 0.58 mg collagenase injection. Results in allparameters after one year were similar to those who received a secondinjection as delineated in FIG. 2. None of these patients were lost to12 month follow-up.

Adverse events were local and minimal consisting of injection areatenderness and biceps ecchymosis. These resolved well in 7-14 days.There were no adverse immune events.

Discussion

This study has shown that collagenase injection for adhesive capsulitisis a novel method for early restoration of shoulder motion, function andpain resolution. The highest dose used (0.58 mg) trended to be the mosteffective in controlled study. However, it was apparent that a shortseries of injections using the 0.58 mg dose was more effective in openlabel study.

Additional Results

It is noted that the use of separate examples is not intended to implythat separate and distinct studies, rather than separate analysis of theresults. The invention, of course, also relates to the use thecollagenase formulations of the invention to achieve the resultsdescribed in these results. The results of these studies also includethe data presented in the following tables: TABLE 1 Means ± standarddeviation for endpoints at baseline and at the 30-day double-blind visitPlacebo 2,500 u 5,000 u 10,000 u (n = 15) (n = 16) (n = 15) (n = 14)Active elevation Treated shoulder at baseline 112.9 ± 21.8 115.0 ± 16.2 109.1 ± 21.4  111.1 ± 20.3  (degrees) Contralateral Shoulder at baseline§ 168.0 ± 9.6  162.4 ± 14.2  170.8 ± 9.0  165.8 ± 16.0  30-day,double-blind observation 125.2 ± 23.6 134.1 ± 22.8  127.8 ± 19.0  139.0± 22.1  Active external Treated shoulder at baseline  25.2 ± 15.3 20.9 ±17.1 29.7 ± 18.9 31.3 ± 14.6 rotation (degrees) Contralateral Shoulderat baseline § 81.7 ± 6.5 73.0 ± 19.8 78.5 ± 11.9 74.7 ± 16.0 30-day,double-blind observation  41.4 ± 17.4 38.2 ± 20.5 54.8 ± 14.9 52.0 ±16.2 Active internal Treated shoulder at baseline  4.9 ± 1.8 5.1 ± 2.45.3 ± 2.4 5.9 ± 2.8 rotation (spine level) Contralateral Shoulder atbaseline § 15.3 ± 3.2 12.9 ± 4.1  13.8 ± 4.1  15.4 ± 2.8  (degrees)30-day, double-blind observation  7.5 ± 2.6 8.3 ± 3.6 8.3 ± 4.0 8.6 ±4.0 Passive elevation Treated shoulder at baseline 127.7 ± 19.5 132.7 ±17.7  125.6 ± 16.3  135.9 ± 14.4  (degrees) Contralateral Shoulder atbaseline § 175.2 ± 7.9  173.9 ± 9.0  176.2 ± 6.8  175.6 ± 9.4  30-day,double-blind observation 143.3 ± 21.8 147.0 ± 20.6  144.9 ± 16.4  150.3± 21.4  Passive external Treated shoulder at baseline  32.8 ± 22.3 23.3± 15.5 29.5 ± 14.8 26.7 ± 18.9 rotation (degrees) Contralateral Shoulderat baseline § 89.6 ± 1.4 80.3 ± 17.1 87.9 ± 5.8  85.8 ± 9.3  30-day,double-blind observation  47.3 ± 19.8 46.6 ± 22.9 56.5 ± 22.2 58.7 ±22.0 Passive external Treated shoulder at baseline  68.0 ± 16.1 70.3 ±14.5 67.0 ± 18.1 72.3 ± 13.2 elevation @ 90° Contralateral Shoulder atbaseline § 102.1 ± 5.1  99.6 ± 15.4 110.7 ± 12.6  102.3 ± 7.6  (degrees)30-day, double-blind observation  83.3 ± 13.6 82.1 ± 13.5 88.7 ± 11.888.9 ± 10.1 Function score (0-60 Treated shoulder at baseline 31.2 ± 9.332.0 ± 7.1  32.9 ± 7.5  31.9 ± 6.8  scale) Contralateral Shoulder atbaseline § 60.0 ± 0.0 60.0 ± 0.0  60.0 ± 0.0  60.0 ± 0.0  30-day,double-blind observation  42.4 ± 12.4 44.2 ± 9.8  49.3 ± 8.8  49.7 ±7.5  Pain score (0-5 Treated shoulder at baseline  2.0 ± 0.8 1.9 ± 0.91.9 ± 0.8 2.3 ± 1.0 scale) Contralateral Shoulder at baseline §  5.0 ±0.0 5.0 ± 0.0 5.0 ± 0.0 5.0 ± 0.0 30-day, double-blind observation  3.3± 0.9 3.8 ± 0.9 3.9 ± 0.9 3.5 ± 0.9§ For contralateral shoulder at baseline, n = 12, 10, 12, and 12 for,respectively, placebo, 2,500 u, 5000 u, and 10,000 u treatments.

TABLE 2 Means ± standard deviation for endpoints at the 30-day visitafter the first and second open-label treatments Open-label treatment ofRandomization group 10,000 u Placebo 2,500 u 5,000 u 10,000 u Activeelevation First § 143.6 ± 24.5  146.8 ± 15.5  143.2 ± 18.8 148.8 ± 13.2(degrees) Second ‡ 141.7 ± 18.3  144.1 ± 12.7  152.5 ± 8.7  155.2 ± 4.3 Active external First § 60.2 ± 20.1 46.8 ± 17.1  64.8 ± 18.7  54.8 ±14.7 rotation (degrees) Second ‡ 62.6 ± 19.2 47.1 ± 16.6  61.3 ± 12.2 62.0 ± 13.7 Active internal First § 10.2 ± 3.6  9.2 ± 5.2  9.8 ± 4.210.7 ± 4.9 rotation (spine level) Second ‡ 10.4 ± 4.5  8.4 ± 3.6 12.0 ±7.6  9.2 ± 2.3 (degrees) Passive elevation First § 156.7 ± 22.7  154.3 ±16.1  156.1 ± 19.8 158.1 ± 12.6 (degrees) Second ‡ 158.7 ± 16.5  152.9 ±14.0  167.0 ± 9.5  164.8 ± 8.5  Passive external First § 69.5 ± 22.156.9 ± 24.7  68.9 ± 20.5  60.9 ± 17.5 rotation (degrees) Second ‡ 74.0 ±22.2 53.9 ± 22.5  64.0 ± 16.8 62.3 ± 7.7 Passive external First § 93.7 ±15.9 86.5 ± 9.7  96.6 ± 9.9  93.4 ± 14.0 elevation @ 90° Second ‡ 95.7 ±16.4 85.7 ± 8.4  101.8 ± 7.9  90.7 ± 5.6 (degrees) Function score (0-60First § 51.4 ± 9.1  51.2 ± 6.3  51.2 ± 8.5 52.4 ± 7.0 scale) Second ‡52.6 ± 9.9  53.4 ± 3.8   52.0 ± 10.8 57.7 ± 2.7 Pain score (0-5 scale)First § 3.9 ± 1.0 4.3 ± 0.5  4.1 ± 0.3  4.1 ± 0.9 Second ‡ 3.7 ± 1.0 4.1± 0.7  4.0 ± 0.8  4.3 ± 0.5§ For first open label treatment, n = 13, 12, 9, and 10 for,respectively, placebo, 2,500 u, 5000 u, and 10,000 u treatments, exceptfor active elevation and passive elevation for which n = 9 for the 5000u group.‡ For second open label treatment, n = 7, 7, 4, and 6 for, respectively,placebo, 2,500 u, 5000 u, and 10,000 u treatments.

TABLE 3 Mean change from baseline contralateral shoulder for endpointsat the 30-day visit after the first and second open-label treatmentsOpen-label treatment of Randomization group 10,000 u Placebo 2,500 u5,000 u 10,000 u Active elevation First § −13.9 −18.1 −24.1 −12.4(degrees) Second ‡ −13.5 −15.2 −10.0 −9.0 Active external First § −15.6−32.1 −9.6 −15.6 rotation (degrees) Second ‡ −15.5 −26.8 −18.0 −6.8Active internal First § −3.7 −3.0 −3.3 −5.4 rotation (spine level)Second ‡ −3.3 −4.6 −1.0 −5.6 (degrees) Passive elevation First § −7.8−21.5 −14.1 −17.3 (degrees) Second ‡ −5.0 −19.2 −7.0 −9.6 Passiveexternal First § −11.0 −28.1 −16.4 −23.3 rotation (degrees) Second ‡−2.5 −21.0 −18.0 −20.2 Passive external First § −1.9 −11.6 −14.1 −6.0elevation @ 90° Second ‡ 0.5 −11.2 −16.0 −6.6 (degrees) Fraction score(0-60 First § −4.6 −9.5 −5.4 −8.1 scale) Second ‡ −3.0 −7.0 −2.7 −2.6Pain score (0-5 scale) First § −0.8 −0.8 −0.9 −0.9 Second ‡ −0.8 −0.6−0.7 −0.8§ For first open label treatment, n = 10, 8, 8, and 8 for, respectively,placebo, 2,500 u, 5000 u, and 10,000 u treatments.‡ For second open label treatment, n = 4, 5, 3, and 5 for, respectively,placebo, 2,500 u, 5000 u, and 10,000 u treatments.

TABLE 4 Change from baseline (except success rate) at the 30-day studyvisit Active elevation Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 6.7 9.0 12.27 1 2,500 16 12.51.00 19.5 0.15 19.13 0.19 1 5,000 15 0.0 1.00 22.0 0.30 18.73 0.25 110,000 14 14.3 0.60 26.0 0.02 27.79 0.02 Open-label study phase 2 10,00045 35.0 33.98 3 10,000 24 42.0 39.08 4 10,000 3 17.0 28.33 5 10,000 217.5 17.50

TABLE 5 Change from baseline (except success rate) at the 30-day studyvisit Passive elevation Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 26.7 15.0 15.67 1 2,500 1631.3 1.00 17.0 0.77 14.31 0.79 1 5,000 15 20.0 1.00 20.0 0.87 19.27 0.531 10,000 14 28.6 1.00 16.5 0.66 14.43 0.83 Open-label study phase 210,000 44 30.0 27.56 3 10,000 24 35.5 31.00 4 10,000 3 17.0 25.67 510,000 2 20.5 20.50

TABLE 6 Change from baseline (except success rate) at the 30-day studyvisit Active ER at side Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 46.7 10.0 16.20 1 2,500 1637.5 0.72 19.0 0.62 17.25 0.80 1 5,000 15 73.3 0.26 27.0 0.12 25.13 0.081 10,000 14 71.4 0.26 18.5 0.41 20.71 0.44 Open-label study phase 210,000 44 28.0 30.55 3 10,000 24 34.0 36.79 4 10,000 3 36.0 36.33 510,000 2 30.5 30.50

TABLE 7 Change from baseline (except success rate) at the 30-day studyvisit Passive ER at side Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 60.0 7.0 14.47 1 2,500 16 56.31.00 20.5 0.28 23.31 0.27 1 5,000 15 66.7 1.00 26.0 0.13 27.00 0.11 110,000 14 71.4 0.70 31.5 0.05 32.00 0.03 Open-label study phase 2 10,00044 34.5 35.80 3 10,000 24 31.5 35.54 4 10,000 3 21.0 23.33 5 10,000 219.5 19.50

TABLE 8 Change from baseline (except success rate) at the 30-day studyvisit IR spinal level Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 26.7 3.0 2.67 1 2,500 16 50.00.27 4.0 0.56 3.13 0.60 1 5,000 15 40.0 0.70 2.0 0.88 3.07 0.66 1 10,00014 42.9 0.45 2.0 0.88 2.64 0.98 Open-label study phase 2 10,000 44 5.05.16 3 10,000 24 5.0 5.50 4 10,000 3 4.0 6.33 5 10,000 2 3.5 3.50

TABLE 9 Change from baseline (except success rate) at the 30-day studyvisit Passive ER at 90° Protocol- defined p-value p-value p-valueTreatment Incremental success vs Median vs Mean vs cycle dose n rate (%)placebo (degrees) placebo (degrees) placebo Placebo-controlled,double-blind study phase 1 0 (Placebo) 15 46.7 15.0 15.33 1 2,500 1637.5 0.72 14.5 0.83 11.75 0.53 1 5,000 15 66.7 0.46 20.0 0.22 21.67 0.301 10,000 14 57.1 0.72 15.0 0.73 16.57 0.82 Open-label study phase 210,000 44 21.0 23.80 3 10,000 24 20.0 23.17 4 10,000 3 15.0 20.33 510,000 2 15.0 15.00

TABLE 10 Change from baseline (except success rate) at the 30-day studyvisit Strength Protocol- defined p-value p-value p-value TreatmentIncremental success vs vs vs cycle dose n rate (%) placebo Medianplacebo Mean placebo Placebo-controlled, double-blind study phase 1 0(Placebo) 15 100.0 0 0 1 2,500 16 100.0 0 1.00 0 1 5,000 15 100.0 0 0.180.33 0.16 1 10,000 14 100.0 0 0.16 −0.43 0.16 Open-label study phase 210,000 44 0 −0.05 3 10,000 24 0 −0.08 4 10,000 3 0 0 5 10,000 2 0 0

TABLE 11 Change from baseline (except success rate) at the 30-day studyvisit Stability Protocol- defined p-value p-value p-value TreatmentIncremental success vs vs vs cycle dose n rate (%) placebo Medianplacebo Mean placebo Placebo-controlled, double-blind study phase 1 0(Placebo) 15 100.0 0 0 1 2,500 16 100.0 0 1.00 0 1 5,000 15 100.0 0 1.000 1 10,000 14 100.0 0 0.34 −0.21 0.31 Open-label study phase 2 10,000 440 −0.07 3 10,000 24 0 0 4 10,000 3 0 0 5 10,000 2 0 0

TABLE 12 Change from baseline (except success rate) at the 30-day studyvisit Function Protocol- defined p-value p-value p-value TreatmentIncremental success vs vs vs cycle dose n rate (%) placebo Medianplacebo Mean placebo Placebo-controlled, double-blind study phase 1 0(Placebo) 15 26.7 10.0 11.20 1 2,500 16 25.0 1.00 13.0 0.72 12.19 0.73 15,000 15 46.7 0.45 18.0 0.17 16.40 0.11 1 10,000 14 42.9 0.45 19.0 0.0617.79 0.04 Open-label study phase 2 10,000 44 22.0 20.50 3 10,000 2425.5 22.88 4 10,000 3 26.0 23.67 5 10,000 2 20.5 20.50

TABLE 13 Change from baseline (except success rate) at the 30-day studyvisit Pain Protocol- defined p-value p-value p-value TreatmentIncremental success vs vs vs cycle dose n rate (%) placebo Medianplacebo Mean placebo Placebo-controlled, double-blind study phase 1 0(Placebo) 15 86.7 1.0 1.33 1 2,500 16 87.5 1.00 1.0 0.65 1.44 0.69 15,000 15 93.3 1.00 2.0 0.05 2.00 0.05 1 10,000 14 85.7 1.00 1.0 0.781.21 0.75 Open-label study phase 2 10,000 44 2.0 2.16 3 10,000 24 2.02.13 4 10,000 3 4.0 3.00 5 10,000 2 2.5 2.50

TABLE 14 Change from baseline (except success rate) at the 30-day studyvisit Satisfaction Protocol- defined p-value p-value p-value TreatmentIncremental success vs vs vs cycle dose n rate (%) placebo Medianplacebo Mean placebo Placebo-controlled, double-blind study phase 1 0(Placebo) 15 53.3 1 2,500 16 68.8 0.47 1 5,000 15 66.7 0.71 1 10,000 1478.6 0.25 Open-label study phase 2 10,000 3 10,000 4 10,000 5 10,000

TABLE 15 Open-label phase change from baseline at the 30-day study visitActive elevation Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 28.3 <.0001 2 2,500 12 32.4 <.0001 2 5,000 10 33.6 0.0007 2 10,000 1043.6 <.0001 3 0 (Placebo) 7 34.3 0.0008 3 2,500 7 34.1 0.0023 3 5,000 443.8 0.0089 3 10,000 6 47.3 0.0002

TABLE 16 Open-label phase change from baseline at the 30-day study visitPassive elevation Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 29.2 0.0001 2 2,500 12 23.9 0.0002 2 5,000 10 30.4 0.0022 2 10,000 1026.9 0.0002 3 0 (Placebo) 7 32.7 0.0008 3 2,500 7 25.7 0.0125 3 5,000 433.3 0.0078 3 10,000 6 33.6 0.0020

TABLE 17 Open-label phase change from baseline at the 30-day study visitActive ER at side Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 35.2 <.0001 2 2,500 12 29.0 <.0001 2 5,000 9 29.8 0.0035 2 10,000 1027.0 0.0014 3 0 (Placebo) 7 38.2 0.0004 3 2,500 7 37.1 0.0002 3 5,000 433.7 0.0230 3 10,000 6 36.6 0.0015

TABLE 18 Open-label phase change from baseline at the 30-day study visitPassive ER at side Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 39.6 <.0001 2 2,500 12 31.3 0.0005 2 5,000 9 32.6 0.0008 2 10,000 1039.1 0.0007 3 0 (Placebo) 7 41.1 0.0064 3 2,500 7 26.9 0.0064 3 5,000 432.2 0.0259 3 10,000 6 41.3 0.0030

TABLE 19 Open-label phase change from baseline at the 30-day study visitIR spinal level Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 5.2 <.0001 2 2,500 12 4.3 0.0043 2 5,000 9 5.7 0.0013 2 10,000 10 5.70.0010 3 0 (Placebo) 7 5.0 0.0067 3 2,500 7 4.7 0.0080 3 5,000 4 8.80.0635 3 10,000 6 4.8 0.0081

TABLE 20 Open-label phase change from baseline at the 30-day study visitPassive ER at 90° Open-label study phase Mean change Randomization frombaseline Treatment cycle treatment arm n (degrees) p-value 2 0 (Placebo)13 26.4 <.0001 2 2,500 12 17.3 0.0056 2 5,000 9 28.8 0.0012 2 10,000 1023.7 0.0060 3 0 (Placebo) 7 30.4 0.0030 3 2,500 7 16.0 0.0491 3 5,000 429.2 0.0157 3 10,000 6 19.0 0.0058

TABLE 21 Open-label phase change from baseline at the 30-day study visitStrength Open-label study phase Randomization Mean change Treatmentcycle treatment arm n from baseline p-value 2 0 (Placebo) 13 0 2 2,50012 −0.3 0.3388 2 5,000 9 0.2 0.3466 2 10,000 10 0 3 0 (Placebo) 7 0 32,500 7 −0.3 0.3559 3 5,000 4 0 3 10,000 6 0

TABLE 22 Open-label phase change from baseline at the 30-day study visitStability Open-label study phase Randomization Mean change Treatmentcycle treatment arm n from baseline p-value 2 0 (Placebo) 13 0 2 2,50012 −0.3 0.3388 2 5,000 9 0 2 10,000 10 0 3 0 (Placebo) 7 0 3 2,500 7 0 35,000 4 0 3 10,000 6 0

TABLE 23 Open-label phase change from baseline at the 30-day study visitFunction Open-label study phase Randomization Mean change Treatmentcycle treatment arm n from baseline p-value 2 0 (Placebo) 13 20.6 <.00012 2,500 12 21.0 <.0001 2 5,000 9 18.4 0.0006 2 10,000 10 21.6 <.0001 3 0(Placebo) 7 22.7 0.0037 3 2,500 7 23.1 <.0001 3 5,000 4 15.8 0.1151 310,000 6 27.5 0.0002

TABLE 24 Open-label phase change from baseline at the 30-day study visitPain Open-label study phase Randomization Mean change Treatment cycletreatment arm n from baseline p-value 2 0 (Placebo) 13 2 <.0001 2 2,50012 2.3 <.0001 2 5,000 9 2.4 <.0001 2 10,000 10 1.9 0.0007 3 0 (Placebo)7 1.9 0.0004 3 2,500 7 2.3 0.0007 3 5,000 4 2.0 0.0917 3 10,000 6 2.30.0001

TABLE 25 Change from contralateral shoulder baseline for the 30-daystudy visit Active elevation Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−35.6 1 2,500 10 −33.8 0.8269 1 5,000 12 −38.0 0.7652 1 10,000 12 −26.90.3834 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −13.9 −20.9 2 2,500 8 −18.1 −24.2 2 5,000 8 −24.1 −29.6 210,000 8 −12.4 −18.5 3 0 (Placebo) 4 −13.5 −25.5 3 2,500 5 −15.2 −20.7 35,000 3 −10.0 −10.0 3 10,000 5 −9.0 −20.4

TABLE 26 Change from contralateral shoulder baseline for the 30-daystudy visit Passive elevation Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−24.4 1 2,500 10 −30.6 0.3050 1 5,000 12 −26.8 0.6892 1 10,000 12 −25.30.9127 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −7.8 −11.9 2 2,500 8 −21.5 −27.7 2 5,000 8 −14.1 −20.2 210,000 8 −17.3 −22.9 3 0 (Placebo) 4 −5.0 −12.9 3 2,500 5 −19.2 −24.2 35,000 3 −7.0 −15.2 3 10,000 5 −9.6 −18.4

TABLE 27 Change from contralateral shoulder baseline for the 30-daystudy visit Active ER at side Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−35.8 1 2,500 10 −40.8 0.5358 1 5,000 12 −20.0 0.0120 1 10,000 12 −19.80.0255 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −15.6 −21.8 2 2,500 8 −32.1 −39.2 2 5,000 7 −9.6 −13.7 210,000 8 −15.6 −23.3 3 0 (Placebo) 4 −15.5 −29.9 3 2,500 5 −26.8 −42.1 35,000 3 −18.0 −24.6 3 10,000 5 −6.8 −12.7

TABLE 28 Change from contralateral shoulder baseline for the 30-daystudy visit Passive ER at side Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−35.7 1 2,500 10 −37.0 0.8546 1 5,000 12 −27.5 0.2663 1 10,000 12 −26.30.2017 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −11.0 −16.9 2 2,500 8 −28.1 −37.3 2 5,000 7 −16.4 −25.5 210,000 8 −23.3 −30.8 3 0 (Placebo) 4 −2.5 −10.3 3 2,500 5 −21.0 −32.2 35,000 3 −18.0 −24.6 3 10,000 5 −20.2 −27.8

TABLE 29 Change from contralateral shoulder baseline for the 30-daystudy visit IR spinal level Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−6.9 1 2,500 10 −5.8 0.4766 1 5,000 12 −4.5 0.0917 1 10,000 12 −7.30.7881 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −3.7 −5.9 2 2,500 8 −3.0 −5.7 2 5,000 7 −3.3 −4.8 2 10,0008 −5.4 −7.5 3 0 (Placebo) 4 −3.3 −6.6 3 2,500 5 −4.6 −7.1 3 5,000 3 −1.0−2.1 3 10,000 5 −5.6 −7.5

TABLE 30 Change from contralateral shoulder baseline for the 30-daystudy visit Passive ER at 90° Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−16.2 1 2,500 10 −22.1 0.4676 1 5,000 12 −20.9 0.4260 1 10,000 12 −13.60.6256 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −1.9 −5.7 2 2,500 8 −11.6 −20.5 2 5,000 7 −14.1 −19.6 210,000 8 −6.0 −13.2 3 0 (Placebo) 4 0.5 −6.2 3 2,500 5 −11.2 −21.9 35,000 3 −16 −27.3 3 10,000 5 −6.6 −14.6

TABLE 31 Change from contralateral shoulder baseline for the 30-daystudy visit Strength Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12 01 2,500 10 0 1 5,000 12 0 1 10,000 12 −0.5 0.1775 Open-label study phaseLower limit of one-sided 90% CI 2 0 (Placebo) 10 0 0 2 2,500 8 0 0 25,000 7 0 0 2 10,000 8 0 0 3 0 (Placebo) 4 0 0 3 2,500 5 −0.4 −1.0 35,000 3 0 0 3 10,000 5 0 0

TABLE 32 Change from contralateral shoulder baseline for the 30-daystudy visit Stability Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12 01 2,500 10 0 1 5,000 12 0 1 10,000 12 −0.3 0.3282 Open-label study phaseLower limit of one-sided 90% CI 2 0 (Placebo) 10 0 0 2 2,500 8 0 0 25,000 7 0 0 2 10,000 8 0 0 3 0 (Placebo) 4 0 0 3 2,500 5 0 0 3 5,000 3 00 3 10,000 5 0 0

TABLE 33 Change from contralateral shoulder baseline for the 30-daystudy visit Function Mean change from Treatment Randomizationcontralateral p-value vs cycle treatment arm n baseline (degrees)placebo Placebo-controlled, double-blind study phase 1 0 (Placebo) 12−14.9 1 2,500 10 −16.3 0.7725 1 5,000 12 −7.3 0.0546 1 10,000 12 −10.80.3246 Open-label study phase Lower limit of one-sided 90% CI 2 0(Placebo) 10 −4.6 −7.1 2 2,500 8 −9.5 −12.4 2 5,000 7 −5.4 −8.7 2 10,0008 −8.1 −11.9 3 0 (Placebo) 4 −3.0 −4.8 3 2,500 5 −7.0 −9.9 3 5,000 3−2.7 −4.9 3 10,000 5 −2.6 −4.6

TABLE 34 Change from contralateral shoulder baseline for the 30-daystudy visit Pain Mean change from Treatment Randomization contralateralp-value vs cycle treatment arm n baseline (degrees) placeboPlacebo-controlled, double-blind study phase 1 0 (Placebo) 12 −1.5 12,500 10 −1.8 0.4508 1 5,000 12 −0.8 0.0580 1 10,000 12 −1.5 1.0000Open-label study phase Lower limit of one-sided 90% CI 2 0 (Placebo) 10−0.8 −1.1 2 2,500 8 −0.8 −1.0 2 5,000 7 −0.9 −1.1 2 10,000 8 −0.9 −1.4 30 (Placebo) 4 −0.8 −1.2 3 2,500 5 −0.6 −1.0 3 5,000 3 −0.7 −1.3 3 10,0005 −0.8 −1.1

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A method of treating or preventing adhesive capsulitis in a subjectin need of such treatment comprising delivering an effective amount ofcollagenase to collagenous adhesions in the shoulder.
 2. The methodaccording to claim 1, wherein the collagenase is derived fromClostridium histolyticum.
 3. The method according to claim 2, whereinthe collagenase is injected in a dose comprising at least about 700 SRCunits.
 4. The method according to claim 3, wherein the collagenase isinjected in a volume of less than 0.5 ml.
 5. The method according toclaim 3, wherein the collagenase comprises collagenase I and collagenaseII.
 6. The method according to claim 4, wherein the injection isdelivered in a single injection between the interval of the deltoid andpectoral muscles.
 7. The method according to claim 1, wherein thesubject is a human patient.
 8. The method according to claim 7, whereinthe patient is characterized by an active forward elevation of only 90degrees and an active external rotation of less than 50 degrees.
 9. Themethod according to claim 1, wherein after one month of receiving atleast one administration of collagenase, the patient achieves an activeexternal rotation of greater than 15°, as compared to baseline.